The influence of the prethymic compartment on the acquisition of tolerance to foreign antigens was evaluated by varying the foreign antigens to which precursor T cells are exposed in their pre-thymic environment. The experimental model consists of a host mouse which received a thymus graft followed by lethal radiation and reconstitution with bone marrow cells of the same MHC haplotype as the thymus graft. Thus, bone marrow derived stem cells are maturing in an MHC syngeneic thymus but can be exposed to novel MHC and non-MHC antigens prethymically by varying the genetic origin of the host mouse. The thymocytes from such experimental mice are then assayed for their reactivity against the foreign antigens which they encountered prior to their entry into the thymus. It was found that thymocytes are tolerant to foreign MHC determinants encountered pre-thymically, but appear not to be tolerant to foreign non-MHC determinants encountered pre-thymically. Thus, these results suggest that thymocytes pre-thymically express receptors specific for MHC determinants but may not pre-thymically express receptors specific for non-MHC determinants.